Structure–activity relationship studies of the natural product cystobactamid at four different positions led to novel imaging probes and analogs with superior antibacterial activities and in vivo efficacy.

Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad‐spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor‐groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919‐2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram‐negative bacteria.

While a drug treatment is unavailable, the global incidence of Dengue virus (DENV) infections and its associated severe manifestations continues to rise. We report the construction of the first physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that predicts viremia levels in relevant target organs based on preclinical data with the broad spectrum antiviral soraphen A (SorA), an inhibitor of the host cell target acetyl-CoA-carboxylase. SorA was highly effective against DENV in vitro (EC50 = 4.7 nM) and showed in vivo efficacy by inducing a significant reduction of viral load in the spleen and liver of IFNAR–/– mice infected with DENV-2. PBPK/PD predictions for SorA matched well with the experimental infection data. Transfer to a human PBPK/PD model for DENV to mimic a clinical scenario predicted a reduction in viremia by more than one log10 unit for an intravenous infusion regimen of SorA. The PBPK/PD model is applicable to any DENV drug lead and, thus, represents a valuable tool to accelerate and facilitate DENV drug discovery and development.

Optimization of the natural antibiotic cystobactamid 507 targeting DNA gyrase and topoisomerase IV was attained by structure– and conformation—activity relationship studies. The bioactive conformation was recognized as syn using conformationally locked analogues via intramolecular hydrogen bonds. The new compounds displayed improved target inhibition, antibacterial activity, stability to metabolism and the resistance factor AlbD. Mode of action study revealed that cystobactamids bind to the DNA part of the gyrase–DNA complex at the minor groove with no intercalation. More information can be found in the Full Paper by R. W. Hartmann et al. on page 7219.